Salivary gland dysfunction occurs as a result of pathological injury after radiotherapy for head and neck cancer as well as due to the autoimmune disease Sjgren's Syndrome and significantly compromises the oral health and quality of life of patients. A potential regenerative approach for restoring salivary function is sem cell therapy, where autologous stem/progenitor cells are transplanted into the injured organ or stem cells within the tissue are reactivated. However, despite the vast majority of patients with salivary dysfunction aged 45yrs or older and the well described adverse alterations in salivary gland structure and function that occurs with increasing age, the effects of aging on stem cell behavior during salivary gland homeostasis and regeneration are not known. In this application we propose to determine the impact of aging on the homeostatic and regenerative function of salivary progenitor cells and their regulation by the parasympathetic nervous system. Parasympathetic nerves are essential to salivary function and regeneration, as well as for the maintenance of epithelial progenitor cells, but very little is known regarding the influence of aging on the functional innervation of these organs. Given that aging is often associated with acinar atrophy and reduced peripheral nerve function, we hypothesize that aging disrupts cholinergic-stem cell communication required to maintain tissue homeostasis and mediate organ regeneration after injury. In this proposal we will address our central hypothesis via two specific aims: 1) Define the effect of aging on the homeostatic and regenerative capacity of SOX2+ progenitor cells and their regulation by parasympathetic nerves and 2) Identify molecular and phenotypic alterations in SOX2+ progenitor cells during aging. These aims will be achieved using a combination of human salivary glands and mouse genetics in conjunction with genetic, biochemical, immunochemical, and high resolution imaging techniques. Our rationale for investigating this hypothesis is that understanding the effects of aging on the homeostastic and regenerative capacity of stem/progenitor cells and on processes that regulate their behavior is vital to their therapeutic application in reversing salivary dysfunction.